Impact of Flavors on Nicotine Perception and Self-Administration via E-Cigarette 1. ABSTRACT Flavors, except for menthol, are prohibited at characterizing levels in combustible cigarettes, due to concerns for their role in facilitation and maintenance of tobacco use. However, flavors are widely available and increase the appeal of e-cigarettes and other tobacco products. Mechanisms by which flavors impact the initiation and maintenance of tobacco use are not well understood. Preclinical and clinical studies have demonstrated that nicotine, the addictive ingredient of tobacco, produces dissociable reinforcing and aversive actions. Based on existing evidence and our own pilot data, we propose that modulation of both the aversive and reinforcing effects of nicotine may represent two broad behavioral mechanisms that underlie the impact of flavors on tobacco use. Accordingly, flavors may enhance the appeal and facilitate development of addiction to tobacco products through modulation of nicotine's' reinforcing or aversive actions. Highly palatable flavors (e.g., fruit) may promote use of tobacco products through their primary reinforcing properties. Since low levels of nicotine have minimal aversive effects, the reinforcing effects of palatable flavors (e.g., fruit) may be more marked at low nicotine doses. In contrast, menthol counters nicotine's aversive irritant qualities, which are exacerbated at higher nicotine doses. Therefore, menthol may be more effective than other flavors at enhancing the appeal of tobacco products containing moderate to high doses of nicotine. In response to FDA RFA-OD-18-002, we propose a human laboratory study that will systematically examine if menthol and fruit flavors impact e-cigarette use through dissociable behavioral mechanisms and exert their effects differentially across nicotine doses. The proposed study uses directed and ad libitum e- cigarette self-administration paradigms to evaluate the impact of flavors (menthol (Menthol, Menthol-Mint), fruit (Green Apple, Watermelon), unflavored) on subjective responses to and self-administration patterns of e- cigarettes containing a range of nicotine concentrations (0, 6, 12, 24 mg/ml), in young adults. This application will further probe these hypothesized behavioral mechanisms and their potential impacts on vulnerable subpopulations of tobacco users by exploring the impact of sex and sensitivity to nicotine aversiveness or bitterness (as operationalized by genetic variations in the ?5 subunit of nicotinic acetylcholine receptor that influences the aversive effects of nicotine, or a taste receptor TAS2R38 important for bitterness perception, respectively) on the study outcomes.